Geographic EBV variants confound disease-specific variant interpretation and predict variable immune therapy responses
Year: 2024
Type: article
Abstract: ABSTRACT: Epstein-Barr virus (EBV) is a potent carcinogen linked to hematologic and solid malignancies and causes significant global morbidity and mortality. Therapy using allogeneic EBV-specific lymphocytes shows promise in certain populations, but the impact of EBV genome variation on these strategies remains unexplored. To address this, we sequenced 217 EBV genomes, including hematologic malignancies from Guatemala, Peru, Malawi, and Taiwan, and analyzed them alongside 1307 publicly available EBV genomes from cancer, nonmalignant diseases, and healthy individuals across Africa, Asia, Europe, North America, and South America. These included, to our knowledge, the first natural killer (NK)/T-cell lymphoma (NKTCL) EBV genomes reported outside of East Asia. Our findings indicate that previously proposed EBV genome variants specific to certain cancer types are more closely tied to geographic origin than to cancer histology. This included variants previously reported to be specific to NKTCL but were prevalent in EBV genomes from other cancer types and healthy individuals in East Asia. After controlling for geographic region, we did identify multiple NKTCL-specific variants associated with a 7.8-fold to 21.9-fold increased risk. We also observed frequent variations in EBV genomes that affected peptide sequences previously reported to bind common major histocompatibility complex alleles. Finally, we found several nonsynonymous variants spanning the coding sequences of current vaccine targets BALF4, BKRF2, BLLF1, BXLF2, BZLF1, and BZLF2. These results highlight the need to consider geographic variation in EBV genomes when devising strategies for exploiting adaptive immune responses against EBV-related cancers, ensuring greater global effectiveness and equity in prevention and treatment.
Source: Blood Advances
Authors: Edward L. Briercheck, Shashidhar Ravishankar, Elshafa Hassan Ahmed, César Camilo Carías Alvarado, Juan Carlos Barrios Menéndez, Oscar Silva, Elizabeth Solórzano-Ortiz, Marcos Mauricio Siliézar Tala, Philip Stevenson, Yuexin Xu, Anthony Wilder Wohns, Daniel Enriquez-Vera, Carlos Barrionuevo, Shan-Chi Yu, Aharon G. Freud, Christopher Oakes, Christoph Weigel, David M. Weinstock, Haley L. Klimaszewski, Apollinaire Ngankeu, Nora Mutalima, Gabriela Samayoa-Reyes, Robert Newton, Rosemary Rochford, Fabiola Valvert, Yasodha Natkunam, Andrei Shustov, Robert A. Baiocchi, Edus H. Warren
Institutions: University of Washington, Fred Hutch Cancer Center, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Liga Nacional Contra el Cáncer, Stanford Medicine, Stanford University, Instituto Nacional de Enfermedades Neoplásicas, National Taiwan University Hospital, The Ohio State University, Dana-Farber Cancer Institute, University of York, University of Colorado Anschutz
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,000
Awards: High-Performance Compute Cluster for Comprehensive Cancer and Infectious Diseases Research, G2637360054, G4266498966, HEMATOLOGY TRAINING, G4660785451, Dissecting the Kaposi Sarcoma Tumor Microenvironment at the Single Cell Level, G6991935933, G7425299926, G834931733, G9000085113, Cancer Center Support Grant
OpenAlex ID: W4399167110